The etiology of psychiatric disorders such as Major Depressive Disorder (MDD) has genetic, environmental, and epigenetic components. The epigenetic component has received very little attention to date but is likely to involve pathological abnormalities in genomic methylation patterns that regulate genes involved in the development or physiology of the brain. There has been little progress in identifying the inherited risk factors for depression or the mechanisms by which environmental factors influence the development of depression. Study of the epigenetic profile of depression will lead to the identification of epigenetic variants that contribute to the disease state, bridging the gap between the genetic and environmental components. The goal of this project is to profile the epigenetic state of DNA methylation and identify novel genes and pathways involved in the etiology of MDD. 1. Identify promoter-associated DNA methylation variants in MDD. I hypothesize that certain inherited epigenetic variants in DNA methylation profiles are associated with an increased risk of developing depression. Preliminary studies have probed the whole-genome DNA methylation state of the ventral prefrontal cortex in MDD cases and a control and identified over 200 candidate genes with differential methylation. From this list genes with a known or hypothesized role in MDD or central nervous system (CNS) function will be selected for validation in a large panel of MDD cases and controls. This work will identify gene-associated methylation variants correlated with MDD. 2. Determine whether methylation variants are inherited or acquired changes. My working hypothesis is that inherited methylation variants can be distinguished from acquired variants by probing for the existence of the methylation variant in a variety of tissues. Inherited methylation variants will be maintained in every tissue, while acquired variants will only be present in a subset of tissues. 3. Evaluate the relationship between DNA methylation, gene expression and histone modifications. I hypothesize that an inverse correlation exists between promoter methylation levels and gene expression levels. I predict that distinct histone modifications are associated with methylated promoters in controls versus MDD cases. The genes identified by this work will increase our understanding of the factors and pathways that contribute to the risk of depression, a prevalent and costly disability. This will facilitate the development of novel therapeutic targets and the development of diagnostics for depression risk and response to treatment.